Enhanced Macrophages Engulfment by Peptide‐Templated Nanoassemblies Targeting SIRPα and Suppressing Oxidative Stress for Atherosclerosis Pro‐Efferocytotic Therapy

Abstract Prompt removal of apoptotic cells via macrophage‐mediated efferocytosis is an emerging approach for atherosclerosis treatment, because these diseased cells directly contribute to vascular inflammation and secondary necrosis in plaques. Despite blocking CD47 can restore impaired efferocytosis by inhibiting “don't eat me” signals, the currently available CD47 antibody (CD47‐Ab)‐based therapy may accelerate off‐target clearance of healthy cells due to the ubiquitous expression of CD47 on viable cells. Here, a peptide‐templated nanoassembly (PTna‐1) engineered to induce synergistic enhancement of engulfment by macrophages is reported. Through self‐assembled polypeptides with multiple functional motifs, the nanoassembly can specifically target p32‐overexpressing macrophages and bind to the Ig‐V‐like domain of SIRPα but not to CD47, thereby normalizing intraplaque efferocytosis and alleviating persistent inflammation. Concurrently, disassembled PTna‐1 released manganese porphyrins with photoacoustic/magnetic resonance imaging capability to suppress oxidative stress and synergistically enhance macrophage phagocytosis through the RhoA/ROCK1 pathway. Compared with CD47‐Abs, PTna‐1 promoted a more significant reduction in lesion area and plaque stabilization without affecting the incidence of anemia in atherosclerotic mice. Proteomic analysis revealed that PTna‐1 treatment decreased the expression of inflammation‐related proteins in plaques. Overall, these peptide‐driven nanoassemblies employing a SIRPα‐specific blockade strategy provide a distinct paradigm of pro‐efferocytotic therapy for atherosclerosis.